The scavenger receptors SRA-1 and SREC-I cooperate with TLR2 in the recognition of the hepatitis C virus non-structural protein 3 by dendritic cells☆

Backgrounds & Aims

The hepatitis C virus NS3 protein is taken up by myeloid cells in a TLR2-independent manner and activates myeloid cells via TLR2. This study aimed to identify the endocytic receptor(s) involved in the uptake of NS3 by myeloid cells and its relation with TLR2.

Methods

Inhibitors and transfected cells were used to identify the nature of the NS3-binding receptors expressed by myeloid cells. The cooperation between scavenger receptors (SRs) and TLR2 in the NS3-mediated activation of myeloid cells was evaluated using inhibitors, cells from TLR2^−/− mice, and confocal microscopy. The involvement of SRs in NS3 cross-presentation was evaluated in vitro using an NS3-specific human T-cell clone.

Results

We observed that SRs are the main binding structures for NS3 on myeloid cells and identified the SRs SRA-1 and SREC-I as endocytic receptors for NS3. Moreover, both SRs and TLR2 cooperate in NS3-induced myeloid cell activation.

Conclusion

This study highlights a central role for SRs in NS3 uptake and cross-presentation, and demonstrates a tightly orchestrated cooperation between signalling and endocytic innate receptors in NS3 recognition.

Abbreviations: DC, dendritic cell, Mϕ, macrophage, PRR, pattern recognition receptor, PAMP, pathogen-associated molecular pattern, ACAMP, apoptotic cell-associated molecular pattern, SR, scavenger receptor, CLR, C-type lectin receptor, TLR, Toll-like receptor, RIG, retinoic-acid-inducible gene, RLR, RIG-like receptor, NOD, nucleotide oligomerisation domain, NLR, NOD-like receptor, HCV, hepatitis C virus, NS, non-structural protein, IFN, interferon, CTL, cytotoxic T lymphocyte, APC, antigen-presenting-cell, SREC-I, scavenger receptor expressed by endothelial cells, mBSA, maleylated bovine serum albumin, PBMC, peripheral blood mononuclear cell, mDC, myeloid dendritic cell, pDC, plasmacytoid dendritic cell, FACS, fluorescence-activated cell sorting, DiI-Ac-LDL, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate acetylated-low density lipoprotein, LPS, lipopolysaccharide, Ox-LDL, oxidised low density lipoprotein, MFI, mean fluorescence intensity

Keywords: HCV NS3, TLR2, Scavenger receptors, Cross-presentation, Cooperation between innate receptors, Vaccine vector